No abstract

Pediatric high-grade gliomas (pHGGs), encompassing hemispheric and diffuse midline gliomas (DMGs), remain a devastating disease. The last decade has revealed oncogenic drivers including single nucleotide variants (SNVs) in histones. However, the contribution of structural variants (SVs) to gliomagenesis has not been systematically explored due to limitations in early SV analysis approaches. Using SV algorithms, we recently created, we analyzed SVs in whole-genome sequences of 179 pHGGs including a novel cohort of treatment naïve samples-the largest WGS cohort assembled in adult or pediatric glioma. The most recurrent SVs targeted MYC isoforms and receptor tyrosine kinases, including a novel SV amplifying a MYC enhancer in the lncRNA CCDC26 in 12% of DMGs and revealing a more central role for MYC in these cancers than previously known. Applying de novo SV signature discovery, we identified five signatures including three (SVsig1-3) involving primarily simple SVs, and two (SVsig4-5) involving complex, clustered SVs. These SV signatures associated with genetic variants that differed from what was observed for SV signatures in other cancers, suggesting different links to underlying biology. Tumors with simple SV signatures were TP53 wild-type but were enriched with alterations in TP53 pathway members PPM1D and MDM4. Complex signatures were associated with direct aberrations in TP53, CDKN2A, and RB1 early in tumor evolution, and with extrachromosomal amplicons that likely occurred later. All pHGGs exhibited at least one simple SV signature but complex SV signatures were primarily restricted to subsets of H3.3 K27M DMGs and hemispheric pHGGs. Importantly, DMGs with the complex SV signatures SVsig4-5 were associated with shorter overall survival independent of histone type and TP53 status. These data inform the role and impact of SVs in gliomagenesis and mechanisms that shape them.

Healthcare systems in many countries have been overwhelmed by the coronavirus disease (COVID-19) pandemic, with increasing demands to contain and respond to the virus. The result has been increased pressure on frontline health workers. As the pandemic unfolds, the impact on health systems in low-income and middle-income countries (LMICs) is becoming apparent. In lower resource settings, the detrimental effects on frontline health workers will likely be significant due to fragmented infrastructure, low compensation, and significant shortages of necessary resources such as personal protective equipment. These high stress conditions, coupled with risk of infection and fears and anxieties among patients, can result in grave psychosocial consequences for frontline health workers, who play a vital role in delivering the bulk of primary care services in LMICs. In this narrative review, we consider the psychological impact of the COVID-19 pandemic on frontline health workers in LMICs. We describe the important role of frontline health workers, summarize existing literature on burnout and risks to mental health in this essential workforce, and consider how public health emergencies exacerbate these concerns to showcase their vulnerability to mental health impacts of COVID-19. We explore emerging research on the detrimental effects of the COVID-19 pandemic on health workers and consider possible approaches to mitigate these consequences. This review draws from existing studies and emerging evidence to highlight the critical need to consider the wellbeing of frontline health workers, and to address these challenges as health systems respond to the pandemic.